Reactive Oxygen Species (ROS) are Induced by Kaposi's Sarcoma-Associated Herpesvirus Early During Primary Infection of Endothelial Cells to Promote Virus Entry.

Nov 2012

Bottero V, Chakraborty S, Chandran B.

Source

H. M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL.

Abstract

KSHV entry into human dermal microvascular endothelial cells (HMVEC-d), a natural in vivo target cell, via macropinocytosis is initiated through a multistep process involving binding of KSHV envelope glycoproteins with cell surface α3β1, αVβ3 and αVβ5 integrin molecules and tyrosine kinase EphrinA2 receptor followed by the activation of integrin-associated pre-existing signaling molecules such as FAK, Src, c-Cbl, PI3-K and Rho-GTPases. Many viruses, including KSHV, utilize cellular reactive oxygen species (ROS) for viral genomic replication and survival within host cells; however, the role of ROS on early events of viral entry and induction of signaling has not been elucidated. Here we show that KSHV induced ROS production very early during infection of HMVEC-d cells which was sustained over the observed 24 h post-infection. ROS induction was dependent on KSHV binding to the target cells since pretreatment of virus with heparin abolished ROS induction. Pretreatment of HMVEC-d cells with the antioxidant N-Acetyl-Cysteine (NAC) significantly inhibited KSHV entry and consequently gene expression without affecting virus binding. In contrast, H(2)O(2) treatment increased KSHV entry and infection. In addition, NAC inhibited KSHV infection induced translocation of αVβ3 integrin into lipid rafts, actin dependent membrane perturbations such as blebs observed during macropinocytosis and activation of EphrinA2 receptor, FAK, Src and Rac1 signal molecules. In contrast, H(2)O(2) treatment increased the activation of EphrinA2, FAK, Src and Rac1. These studies demonstrate that KSHV infection induces ROS very early during infection to amplify the signaling pathways necessary for its efficient entry via macropinocytosis in HMVEC-d cells.

PubMed

Vaccine prospect of Kaposi sarcoma-associated herpesvirus.

Aug 2012

Wu TT, Qian J, Ang J, Sun R.

Source

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States. twu@mednet.ucla.edu

Abstract

Infection of Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) is estimated to account for 34,000 new cancer cases globally. Unlike other herpesviruses, KSHV is not ubiquitous but is highly prevalent in some areas, such as sub-Saharan Africa where Kaposi sarcoma is the leading cancer among adults. While latent infection of KSHV plays a major and direct role in tumorigenesis, viral lytic replication also makes significant contributions to this process. Efforts to develop a KSHV vaccine are limited, but studies with EBV have provided important lessons. Informative vaccine research has been conducted in the mouse infection model of a closely related rodent virus, murine gammaherpesvirus-68 (MHV-68 or γHV-68). This mouse model has generated fundamental principles for an effective vaccination strategy. KSHV vaccines designed to prevent a naïve host from infection and to boost the immune control of KSHV in persistently infected people will have major impact on individuals who are at a high risk of developing KSHV-associated diseases.

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